PROJECT SUMMARY The long term goal of this project is to advance the modern management of traumatic brain injury (TBI) by performing a single-stage decompressive craniectomy procedure. To accomplish this goal, we propose utilizing bone regenerative medicine and the development of novel bone paste. A novel biomaterial such as we propose will have several benefits: (1) It can be applied at the time of the initial TBI procedure, thus preventing a second cranioplasty procedure to restore the missing skull, (2) it will be temporarily pliable and allow brain swelling and decompression as is physiologically necessary immediately after TBI, (3) as brain swelling resides it will contract and be osteoconductive/osteoinductive promoting natural cranial bone reformation, (4) it will prevent known long- term neurologic deficits associated after craniectomy termed ?syndrome of the trephined?. Decompressive craniectomy is a common life-saving neurosurgical procedure utilized to treat TBI in patients with either closed head injury and/or brain ischemia/stroke. By removing half of the calvarial bone, the brain is ?decompressed? by allowing it to swell beyond the confines of the cranial vault, thus mitigating rising intracranial pressures and preventing cortical injury. As the brain swelling subsides, the unprotected cerebral hemisphere begins to sink beyond its native cranial dimensions, causing neurologic deficits, termed ?syndrome of the trephined.? Symptoms include headaches, depression, and loss of fine motor coordination. These symptoms and deficits are reversible but they require a second-stage cranioplasty procedure to restore the cranial anatomy as treatment. The primary objective of this project is to establish a single-surgery decompressive craniectomy procedure using a novel biomaterial. The chief hypothesis is that application of a novel paste-like natural biomaterial immediately following TBI and craniectomy will not only regenerate the cranial bone without the need for a second procedure, but will prevent the neurological deficits associated with syndrome of the trephined. To test this hypothesis, we propose the following aims: 1) Characterize a rat model of TBI with motor deficits attributed to hemi-craniectomy and 2) Implant a paste-like material immediately following hemi-craniectomy to evaluate bone regeneration and alleviation of neurological symptoms. With expertise in bone regeneration, biomaterials, craniofacial surgery and TBI treatment/animal studies, and clinical translation of technology, our team is uniquely qualified to complete this project. Successful implementation of this technology will advance the treatment of TBI.